A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods
A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods
复制标题
DOI：
10.1038/ncomms4287
复制
发表时间：
2014-02-01
影响因子：
16.6
通讯作者：
Baici, Antonio
中科院分区：
文献类型：
--
作者：
Novinec, Marko;Korenc, Matevz;Baici, Antonio
变构调节剂具有微调酶活性的潜力。因此，靶向变构位点作为药物设计策略越来越受到认可。在这里，我们报告了使用计算方法发现了第一个胶原蛋白溶解半胱氨酸肽酶组织蛋白酶 K 的小分子变构抑制剂，这是治疗骨质疏松症的主要靶点。 NSC13345 分子是通过化合物库与肽酶表面位点的高通量对接来鉴定的，肽酶表面位点通过进化上保守的残基网络（蛋白质部分）连接到活性位点。该复合物的晶体结构表明，NSC13345 与组织蛋白酶 K 上的一个新型变构位点结合。该化合物在存在合成底物的情况下充当双曲线混合修饰剂，它完全抑制胶原蛋白降解，并且对组织蛋白酶 K 相对于相关酶具有良好的选择性。总而言之，这些特性使我们的方法和 NSC13345 成为变构药物设计的有希望的候选者。
Allosteric modifiers have the potential to fine-tune enzyme activity. Therefore, targeting allosteric sites is gaining increasing recognition as a strategy in drug design. Here we report the use of computational methods for the discovery of the first small-molecule allosteric inhibitor of the collagenolytic cysteine peptidase cathepsin K, a major target for the treatment of osteoporosis. The molecule NSC13345 is identified by high-throughput docking of compound libraries to surface sites on the peptidase that are connected to the active site by an evolutionarily conserved network of residues (protein sector). The crystal structure of the complex shows that NSC13345 binds to a novel allosteric site on cathepsin K. The compound acts as a hyperbolic mixed modifier in the presence of a synthetic substrate, it completely inhibits collagen degradation and has good selectivity for cathepsin K over related enzymes. Altogether, these properties qualify our methodology and NSC13345 as promising candidates for allosteric drug design.